Piperidine derivatives with psychotogenic activity



United States Patent N0 Drawing. Filed Dec. 23, 1957, Ser. No. 704,24718 Claims. (Cl. 167- 65) This invention relates to piperidinederivatives. More particularly, this invention is concerned with novelN- alkyl-3-piperidyl glycolates, methods of preparing such compounds,and uses of such compounds.

This application is a continuation-in-part of my copending applicationSerial No. 217,413, filed March 24, 1951, which is in turn acontinuation-in-part of my copending application Serial No. 180,295,filed August 18, 1950; and is also a continuation-in-part of mycopending application Serial No, 321,745, filed November 20, 1952, allnow abandoned.

According to one aspect of the present invention there are providednovel compounds of the formula and nontoxic acid addition salts thereof,wherein R is a lower alkyl group, aralkyl groups such as benzyl",phenethyl, chlorobenzyl, methoxyphenethyl, trimethoxyphenylpropyl andp-aminophenylethyl, and aralkenyl groups such as cinnamyl, and R and Rare phenyl, cycloalkyls such as cyclohexyl and cyclopentyl or thienylgroups. Some of the specific compounds within the scope of thisinvention are N-methyl-3-piperidyl benzilate,N-ethyl-3- piperidylbenzilate, N-propyl-B-piperidyl benzilate, N- methyl-3-piperidylphenylcyclohexyl glycolate, N-ethyl- 3-piperidyl phenylcyclohexylglycolate, N-methyl-S-piperidyl dicyclohexyl glycolate,N-ethyl-3-piperidyl dicyclohexyl glycolate, N-methyl-3-piperidylphenyl-Z-thienyl glycolate, N-methyl-3-piperidyl phenylcyclopentylglycolate, N-ethyl-3-piperidyl phenyleyclopentyl glycolate,N-ethyl-3-piperidyl phenyI-Z-thienyl glycolate, and nontoxic acidaddition salts thereof including the hydrochloride, sulfate, maleate,fumarate, succinate, phosphate, benzoate and tartrate.

These compounds, as nontoxic acid addition salts, are powerfulpsychotogens.

In humans, N-methyl-S-piperidyl benzilate hydrochloride,N-ethyl-3-piperidyl benzilate hydrochloride, N-ethyl- 3-piperidylphenylcyclohexyl glycolate hydrochloride, N-methyl-3-piperidylphenylcyclopentyl glycolate hydrochoride, and N-methyl-3-piperidylphenyl 2-thienyl glycolate hydrochloride have been found to be extremelypowerful hallucinogens. When administered in -15 mg. doses orally tohuman volunteers N-methyl-3-piperidyl benzilate hydrochloride andN-ethyl-S-piperidyl benzilate hydrochloride induced distinct auditoryand visual hallucinations within one hour in each individual and theserecurred periodically for periods up to -10 hours after theadministration of the compound. The hallucinations were accompanied bygross distortions of visual images and severe alterations in feelingstate. Some of the subjects exhibited paranoid and megalomanicdelusions, while the affective states ranged from a feeling ofunpleasantness to extreme terror.

Humans to whom 20 mgm. of N-methyl-3-piperidyl benzilate hydrochlorideand N-ethyl-3-piperidyl benzilate 2,995,492 Patented Aug. 8 1961hydrochloride were given orally were in complete loss of contact withthe environment for many hours while experiencing dramatic visual andauditory hallucinations. Animals such as cats and rodents which receivedthese agents showed marked behavioral changes such as initial excitementand marked hyperactivity, spontaneous squealing, lack of responsivenessto stimuli, muscular weakness and lethargy.

Surprisingly, similar compounds without the hydroxyl group, such asN-ethyl-3-piperidyl diphenylacetate hydrochloride, are lacking inhallucinogenic properties. Furthermore, quaternary salts such asN-methyl-3-piperidyl benzilate methobromide orally administered do notinduce hallucinations.

The compounds of this invention produce a state in humans closelyapproaching schizophrenia. Ceruloplasmin determinations were made onhumans given N-methyl or N-ethyl-3-piperidyl benzilate hydrochloridesince this enzyme was known to be increased in the serum of acuteschizophrenics. Observations indicated that as much as a 50-75%elevation in the blood ceruloplasrnin accompanies the hallucinatoryepisode produced by these agents. Ceruloplasmin increased only whenmarked psychogenic disturbances were apparent and returned to normalshortly after the psychogenic effects disappeared.

The artificial production of hallucinations and the schizophrenia-likesyndrome by the compounds provided by this invention can be, and is,being used by the psychiatrist in his study of these conditions. Bybeing able to quickly induce these conditions in an animal or human itis possible to screen agents to discover those which are antidotes andblock the conditions and can be used in psychotherapeutic treatment. Forexample, it has been found that the hallucinations produced in humans byN-methyl or N-ethyl-3-piperidyl benzilate hydrochloride andN-ethyl-3-piperidyl phenylcyclohexyl glycolate hydrochloride can beblocked by 4-hydroxyethyl-piperazinoethyl benzilate hydrochloride andthat this compound possesses psychotherapeutic properties. The4-hydroxyethyl piperazinoethyl benzilate hydrochloride produced a markedbeneficial effect in all disturbed schizophrenic patients to whom it wasgiven. Psychomotor epileptics who were actively hallucinating whentreated with this compound partly or almost completely lost evidence ofhallucinations. Humans with ulcers, spastic colitis and hypertensionthat exhibited psychogenic disturbances have also responded effectivelyto 4-hydroxyethyl piperazinoethyl benzilate hydrochloride. Four or five20 mgm. doses daily are entirely adequate for these purposes.

The compounds of this invention, such as N-methyl andN-ethyl-3-piperidyl benzilate hydrochloride, N-ethyl- B-piperidylphenylcyclohexyl glycolate hydrochloride, N-methyl-3-piperidylphenylcyclopentyl glycolate hydrochloride, N-methyl-B-piperidylphenyl-Z-thienyl glycolate hydrochloride and the like, are also usefulin the shocklike treatment of mental diseases or psychocatharsisproduced by the psychoanalyst. Patients in whom an intense hallucinatorystate is induced by these substances have shown a considerableimprovement over their previous condition. Depressed and anxiouspatients who complained of psychogenic disorders such as hypertension,colitis and ulcers showed distinct psychogenic improvement after one ortwo episodes induced by the agents of this invention. In addition to thedisappearance of colitis and pains due to ulcer, there was a distinctimprovement in the psychological or feeling state of the individuals ofnontoxic quaternary ammonium salts such as the alkyl halides likemethobromide, are antispasmodics and relieve musculotropic andneurotropic spasm in animals including humans. The compounds have longduration of action and few undesirable side reactions.

The compounds of this invention are conveniently prepared by reacting anN-lower alkyl-3-halopiperidine with a compound of the formula to producethe desired compound of the formula ()H R1 i wherein R, R and R have thesignificance previously assigned.

Some 3-halopiperidines which may be used in this proccss areN-methyl-3-chloropiperidine, N-ethyl-3-chloropiperidine,N-propyl-3-bromopiperidine and N-methyl- 3-bromopiperidine,N-phenethyl-3-chloropiperidine, N-paminophenethyl-3-chloropiperidine andthe like.

Some of the other reactants which may be employed in the process arebenzilic acid, phenylcyclohexyl glycolic acid, dicyclohexyl glycolicacid, phenylcyclopentyl glycolic acid and phenyl' 2-thienyl glycolicacid.

The reaction is conveniently effected by combining the reactants in asuitable inert liquid reaction medium, such as isopropanol, andrefluxing the mixture. After filtering' and concentrating the reactionmixture in vacuo it is added to water, acidified and the unreacted acidremoved with ether. After neutralizing the aqueous layer, the product isextracted with ether and the solution dried. After removing the etherthe free base is obtained by vacuum distillation.

Acid addition salts of the tertiary bases provided by this invention arereadily produced by contacting the free base with a suitable acid in thepresence of a solvent such as acetone, benzene, ethanol, isopropanol andether. Typical acids which may be used are hydrochloric acid, sulfuricacid, citric acid, tartaric acid, succinic acid and benzoic acid.

The following examples illustrate the preparation of specific compoundswithin the scope of this invention.

EXAMPLE 1 N-methyI-3-piperidyl benzilate 1 /Q a Q EH:

A mixture containing 8 g. (0.06 mole) of N-methyl- 3-chloropiperidineand 13.6 g. (0.06 mole) of benzilic acid in 50 cc. of anhydrousisopropyl alcohol was refluxed for 3 days; the isopropyl alcohol wasremoved by distillation in vacuo, the residue treated with diluteaqueous hydrochloric acid and the aqueous acid mixture extractedrepeatedly with ether. The aqueous phase was separated, madestronglyalkaline with 20% aqueous sodium hydroxide and extracted with ether. Theether extracts were dried with potassium carbonate and distilled; theproduct was collected at 175-176 C. (0.03 mm.); yield 11.5 g. (59%).

4 EXAMPLE 2 N-methyl-3-piperidyl benzilale hydrochloride /Q a Q EH1 Thefree base of Examplel was dissolved in isopropyl alcohol and thesolution acidified to pH 3 with ethereal hydrochloric acid. Thehydrochloride salt precipitated out on cooling, yield 25 g. (84%), MP.212-213 C.

Analysis.Calcd. for C H CINO Cl, 9.78; N, 3.87. Found: Cl, 9.73; N,3.76.

EXAMPLE 3 N-ethyl-3-piperidyl benzilate v 0-Zg0 i...

N-ethyl-chloropipieridine was prepared according to the method of Fusonand Zirkle described in volume 70, J. Am. Chem. Soc., page 2760.

12.0 grams (0.081 mole) of N-ethyd-B-chloropiperidine was mixed with18.6 g. (0.081 mole) of benzilic acid and 80 cc. of anhydrous isopropylalcohol as a solvent. The mixture was refluxed for seventy-two hours.The solution was then filtered and concentrated at 30 mm. of mercury.The concentrate was dissolved in water, acidified. with hydrochloricacid and extracted with ether to remove the unreacted benzilic acid.

The aqueous layer was neutralized with sodium bicarbonate and theproduct was extracted with ether. The ethereal solution of the productwas dried with potassium carbonate, the ether was removed bydistillation and the residue was distilled at 0.120.18 mm. of mercury,the boiling point being 194-198 C. Ayield of 16.5 g. of the compound wasobtained.

EXAMPLE 4 N-ethyl-S-piperidyl benzilate hydrochloride HCL 6.4 grams ofthe free base from Example 3 was dissolved in acetone and etherealhydrochloric acid added. A yield of 6.2 g. of white crystals melting at186-187 C. was obtained.

Analysis.Calcd. for C, H ClNO,: Cl, 9.45%; N, 3.72. Found: Cl, 9.29%; N,3.62.

EXAMPLE 5 N-ethyl-3-piperidyl phenylcyclohexyl glycolate i and itshydrochloride A mixture containing 31 g. (0.13 mole) of phenylcyclohcxylglycolic acid, 25 g..( 0.17 mole) of N-ethyl-3-chloropipendine and cc.of dry isopropyl alcohol was refluxed for 3 days; the solvent wasremoved by vacuum distillation and the residue suspended-in water. Theaqueous suspension was-acidified with hydrochloric acid, extracted withether and the aqueous phase made alkaline with 12 g. of sodiumhydroxide. The alkaline mixture was extracted with ether, the etherextracts dried with K CO and the ether removed by distillation. The basewas distilled at l66-167 C. (0.05 mm.); yield 24 g. (53%).

The hydrochloride salt was prepared by the addition of etherealhydrochloric acid solution to an acetone solution of the base. Thewhite, crystalline precipitate was removed by filtration, yield' 25 g.(94%); M.P. 213- 215 C.

AnaIysis.Ca1cd. for C H C1NO Cl, 9.30; N, 3.67. Found: Cl, 9.11; N,3.66.

EXAMPLE 6 N-ethyl-3-piperidyl-phenyl-cyclopentyl-glycolate hydrochlorideg lf/Q A mixture of 12.4 g. (0.056 mole) of phenyl-cyclopentyl glycolicacid, 8.3 g. (0.056 mole) N-ethyl-3-chloropiperidine and 50 cc. of dryisopropyl alcohol, as a solvent, was refluxed for 48 hours. The solventwas then removed by distillation in vacuum of the order of 15 mm. Hg.The residue was partially dissolved in aqueous hydrochloric acid and wasrepeatedly extracted with ether. The aqueous layer was separated, madealkaline with 20% sodium hydroxide and again extracted with ether. Theether extract was-dried over anhydrous potassium carbonate at roomtemperature, filtered, and the ether removed by distillation at 35 C.Any low boiling materials were removed by distillation at a pressurereduced to 0.3 Hg and at an oil bath temperature of 170 C. Theresidue'was dissolved in acetone 'and acidified with 9.6 cc. of 3.77 Methereal hydrochloric acid. A white precipitate formed whichwasfiltered, washed with acetone and dried at 80 C. A yield of 11.0 g. (82%of theoretical) was obtained; MEP. of the product was 205207 C. Afterrecrystallization from isopropyl alcohol, the compound melted at 206-208C.

Analysis.-Calcd. for C H CINO Cl, 9.66; N, 3.81. Found: Cl, 9.61; N,3.70.

EXAMPLE 7 N-ethyl-3-piperidyl-phenyI-Z-thimyl-glycolate hydrochlorideOoii-Z Equimolar amounts of N-ethyl-3-chloropiperidine andphenyl-2-thienyl glycolate were reacted in anhydrous isopropyl alcoholat reflux for 48 hours. The mixture was concentrated in vacuum of 15 mm.Hg. The residue was dissolved in an excess of aqueous hydrochloric acidand extracted with ether. The aqueous acid solution was neutralized with20% aqueous sodium hydroxide solution and extracted with ether. Theether extract was dried over anhydrous potassium carbonate at roomtemperature, filtered and distilled to remove the ether. The basic esterwas distilled, dissolved in 100 cc. of acetone and acidified withethereal hydrochloric acid to yield a precipitate. The pgcipitate wasfiltered, washed with acetone and dried at 80 C.

The compound was obtained in 18% yield and had a melting point of181-182" C.

Analysis.Calcd. for C H CINO S: Cl, 9.30%; N, 3.67%. Found: Cl, 9.19; N,3.67%.

The psychotogens of this invention may be administered to animals andhumans as pure compounds. It is advisable, however, to first combine oneor more of the compounds with a suitable pharmaceutical carrier toattain a more satisfactory size to dosage relationship.

Pharmaceutical carrier's which are liquid or solid may be used. Thepreferred liquid carrier is water. Flavoring materials may be includedin the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar, talc, and the like,may be used to form powders. The powders may be used as such or betableted, or be used to fill gelatin capsules. Suitable lubricants likemagnesium stearate, binders such as gelatin and disintegrating agentslike sodium carbonate in combination with citric acid may be used toform the tablets.

Unit dosage forms such as tablets and capsules may contain any suitablepredetermined amount of one or more of the psychotogens and may beadministered one or more at a time at regular intervals. Such formsshould, however, generally contain a minimum concentration of 0.1% to10% by weight of the psychotogen.

A typical tablet may have the composition:

Mg. (1) N-methyl-S-piperidyl benzilate hydroch1oride 10 (2) Starch,U.S.P 57 (3) Lactose, U.S.P 1 73 (4) Talc, U.S.P 9 (5) Stearic acid 6Powders 1, 2 and 3 are slugged, then granulated, nixed with 4 and 5, andtableted.

Tablets may also be made of the following ingredients from the statedquantities:

Grams (1 N-ethyl-3 -piperidyl benzilate hydrochloride 2000 (2) Lactose,U.S.P 800 (3) Dibasic calcium phosphate, U.S.P 1527.2 (4) Starch, U.S.P799.3 (5) Calcium stearate 56.7 (6) Gelatin solution-1.5 lb./gal.- of H0 Lactose, U.S.P 200 Starch, U.S.P 16 Talc, U.S.P 8

The most active compound appears to be N-ethyl-3- piperidylphenylcyclohexyl glycolate hydrochloride and it is effective at a totaldose of 2 to 5 mgm. orally. The other psychotogens produce the statedefiects in doses ranging from 5 to 20 mgm. orally The duration of sucheffects vary from a minimum of a few hours for N- methyl-S-piperidylphenyl-Z-thienyl glycolate. hydrochloride to over 24 hours in the caseof N-ethyl-3- piperidyl phenylcyclohexyl glycolate hydrochloride. Asused herein psychotogens means compounds or compositions which induce,supplement, or amplify in humans and animals a state comparable orsimilar to the manifestations observed in a diseased mind. Psychotogenieis the adjective form of psychotogens.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorpo- 7 rate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. N-methyl-3-piperidyl phcnylcyclohexyl glycolate.

2. N-ethyl-3-piperidyl phenylcyclohexyl glycolate.

3. N-ethyl-3-piperidyl phenylcyclohexyl glycolate hydrochloride.

4; N-methyl-3-piperidyl phenylcyclohexyl glycolate hydrochlon'de.

5. The nontoxic acid addition salts of N-Iower alkyl- 3-piperidylphenylcyclohexyl glycolates.

6. N-lower alkyl-3-piperidyl phenylcycloalkyl gly olate.

7. N-lower alkyl-3-piperidyl phenylcyclopentyl glycolate.

8. N-methyl-B-piperidyl phenylcyclopentyl glycolate hydrochloride.

9. A pharmaceutical tablet containing a nontoxic acid addition salt ofN-methyl-3-piperidyl phenylcyclopentyl glycolate.

10. A pharmaceutical tablet containing a nontoxic acid addition salt ofN-ethyl-S-pipcridyl phenylcyclohexyl glycolate.

11. The method of inducing a psychotogenic state in humans and animalswhich comprises administering to and nontoxic acid addition saltsthereof, wherein R is a member of the group consisting of lower alkyl,phenyllower alkyl and phenyl-lower alkenyl, R is a member of the groupconsisting of phenyl, cycloalkyl and thienyl and R is a member of thegroup consisting of cycloalkyl and thienyl but is not thienyl when R isphenyl.

16. A pharmaceutical composition comprising a nontoxic acid additionsalt of a compound of the formula enemas wherein R is a member of thegroup consisting oflower alkyl, pheuyl-lower alkyl and phcnyl-loweralkenyl, R is a member of the group consisting of phenyl, cycloalkyl andthienyl and R is" a member of the group consisting of cycloalkyl andthienyl but is not thienyl when R is phenyl, and in inert pharmaceuticalcarrier.

17. A composition according to claim 16 in which the carrier is a solid.

18; The method of inducing a psychotogenicstate in humans and animalswhich comprises administering to them an efiective amount of a compoundof the formula and nontoxic acid addition salts thereof,.wherein- R is amember of the group consisting of lower alkyl, phenyllower alkyl andphenyl-lower alkenyl, R is a member of the group consisting of phenyl,cycloalkyl and thienyl and R is a member of the group consisting ofcycloalkyl and thienyl but is not thienyl when R is phenyl.

References Cited in the file of this patent UNITED STATES RATENTS2,167,351 Eisleb July 25, 1939 2,265,185 Miescher Dec. 9, 1941 2,477,937Paul Aug. 2, 1949 2,486,794 Miescher Nov. 1, 1949 2,553,002 FeldkampDec. 5, 1950 2,648,667 Steinbach Aug. 11, 1953 2,792,399 Ekenstam et al.May'14, 1957 2,816,895 Ehrhart Dec. 17, 1957 2,844,591 Feldkamp et alJuly 22, 1958 2,918,406 Biel Dec. 22, 1959 2,918,408 Biel Dec. 22, 1959FOREIGN PATENTS 448,181 Great Britain May 25, 1936 483,258 Great BritainApr. 14, 1938 OTHER REFERENCES McElvain et al.: J.A.C.S., vol. 10, pp.1826-1828, 1948.

Biel et al.: J.A.C.S., vol. 74, pp. 1485-1488, 1952.

Richters Organic Chemistry, v01.' 13, Blakistons Son and Co., 1923, pp.3-4.

Blicke et al.: J.A.C.S., vol. 64, February 1942, pp. 431-433.

Ford-Moore et al.: I Cheml Soc. (London), Part I, (1947), pp. -60.

' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N0.2,995,492. August 8, 1961 John H. Biel It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 4, line 6, right-hand portion of the formula, for HCL" read .HClcolumn 5, lines 58 to 60, the lower I righthand portion of the formulashould appear as shown below instead of as in the patent:

column 6, line 3-4, for "nixed" read mixed line 64, after "orally"insert a period; column 8, line 6, for "in" read an line 34, for"2,553,002" read 2,533,002 same column 8, line 35, for "Steinbach" readSternloach Signed and sealed this 2nd day of January 1962..

(SEAL) Attest: ERNEST W. SWIDER Attesting Officer DAVID L. LADDCommissioner of Patents

16. A PHARMACEUTICAL COMPOSITION COMPRISING A NONTOXIC ACID ADDITIONSALT OF A COMPOUND OF THE FORMULA